Composition and method for inhibiting uptake of biguanide disinfectants by poly(ethylene)

ABSTRACT

The invention provides a method for inhibiting the binding of a biguanide disinfectant in aqueous solution to a poly(ethylene) solid in contact with said solution comprising providing in said solution an amount of cyclodextrin sufficient to inhibit binding of the biguanide disinfectant to the poly(ethylene) solid.

FIELD OF THE INVENTION

This invention relates generally to a composition and method forstoring, preserving and dispensing solutions for cleaning anddisinfecting contact lenses.

BACKGROUND

Biguanide disinfectants such as alexidine and PHMB are widely used asantimicrobials in ophthalmic solutions, for example, contact lenscleaning, disinfecting and have been commercialized in various products,typically at levels of about 1 ppm or less for use with soft contactlenses. It is generally desirable to provide the lowest possible levelof antimicrobial that is consistent with reliable disinfection in orderto provide a generous margin for safety and comfort.

U.S. Pat. No. 4,758,595 to Ogunbiyi et al. discloses a contact-lenssolution containing a polyaminopropyl biguanide (PAPB), also known aspolyhexamethylene biguanide (PHMB) in combination with a borate buffer.These disinfecting and preservative solutions are especially noteworthyfor their broad spectrum of bactericidal and fungicidal activity at lowconcentrations coupled with very low toxicity when used with soft-typecontact lenses.

Some of the most popular products for disinfecting lenses aremultipurpose solutions that can be used to clean, disinfect and wetcontact lenses, followed by direct insertion (placement on the eye)without rinsing. Obviously, the ability to use a single solution forcontact-lens care is an advantage. Such a solution, however, must beparticularly gentle to the eye, since, as indicated above, some of thesolution will be on the lens when inserted and will come into contactwith the eye.

With conventional contact-lens cleaners or disinfectants, includingmulti-purpose solutions, lens wearers typically need to digitally ormanually rub the contact lenses (typically between a finger and palm orbetween fingers) during treatment of the contact lenses. The necessityfor the daily “rubbing” of contact lenses adds to the time and effortinvolved in the daily care of contact lenses. Many contact-lens wearersdislike having to perform such a regimen or consider it to be aninconvenience. Some wearers may be negligent in the proper “rubbing”regimen, which may result in contact-lens discomfort and other problems.Sometimes rubbing, if performed too rigorously, which is particularlyapt to occur with beginning lens wearers, may damage the lenses. Thiscan be problematic when a replacement lens is not immediately available.

Contact lens solutions that qualify as a “Chemical DisinfectingSolution” do not require rubbing to meet biocidal performance criteria(for destroying representative bacteria and fungi) set by the US Foodand Drug Administration (FDA) under the Premarket Notification (510k)Guidance Document For Contact Lens Care Products, May 1, 1997. Incontrast, a contact-lens solution, referred to as a “ChemicalDisinfecting System,” that does not qualify as a Chemical DisinfectingSolution, requires a rubbing regimen to pass biocidal performancecriteria. Traditionally, multi-purpose solutions (used for disinfectingand wetting or for disinfecting, cleaning, and wetting) have qualifiedas a Chemical Disinfecting System, but not as a Chemical DisinfectingSolution.

A Chemical Disinfecting Solution would generally require a moreefficacious or stronger disinfectant than a Chemical DisinfectingSystem. The stronger the biocidal effect of a solution, however, themore likely that it may exhibit toxic effects or adversely effectlens-wearer comfort. For example, many very efficacious bactericidesused in other contexts, such as mouthwashes, cosmetics, or shampoos,while being sufficiently safe for use in such products, would be tootoxic for ophthalmic use, especially for use with soft lenses because ofthe above-mentioned tendency of soft lenses to bind chemicals and thesensitivity of eye tissues. Similarly, the concentrations of certainbactericides may need to be within lower limits in solutions for usewith soft contact lenses than in other products or in solutions forother types of lenses, especially when such solutions are not rinsedfrom the contact lens before placing the lens in the eye.

The solution further needs to be stable over the shelf life of theproduct. U.S. Pat. No. 6,180,093 to De et al. notes that interactionbetween small low-density poly(ethylene) (LDPE) containers and certainantimicrobials may reduce the efficacy of the antimicrobials.

It would be desirable to obtain a contact-lens solution that wouldsimultaneously provide both (1) an increased level and/or broaderspectrum of biocidal activity, and (2) a low order of toxicity to eyetissue, such that the solution can be used to treat a contact lens suchthat the lens can subsequently be placed on the eye without rinsing thesolution from the lens. While challenging to develop, it would beespecially desirable to obtain a Chemical Disinfecting Solution thatcould be used for soft contact lenses and that would allow directplacement of a contact lens on an eye following soaking in the solutionand/or rinsing and rewetting with the solution. Such a product mayprovide increased efficacy, resulting in greater protection to the lenswearer against infection caused by microorganisms, while providingmaximum convenience. Finally, it would be desirable for the biocidalefficacy of the disinfecting solution to be sufficiently high to achievethe efficacious disinfection, or at least not inherently inefficaciousdisinfection, of a contact lens with respect to bacteria and fungi inthe event, for whatever reason, that the contact lens wearer does notcarry out a regimen involving mechanical rubbing or the like using thecontact-lens solution.

SUMMARY OF THE INVENTION

The invention provides, in a first aspect, a method and composition forinhibiting the binding of a biguanide disinfectant in aqueous solutionto a poly(ethylene) solid in contact with said solution comprisingproviding in said solution an amount of cyclodextrin sufficient toinhibit binding of the biguanide disinfectant to the poly(ethylene)solid. The composition of the invention may comprise additionalcomponents, for example, at least one selected from the group consistingof buffers, sequestering and/or chelating agents, tonicity adjustingagents, surfactants, pH adjusting agents and viscosity builders.

The invention also provides a method and composition for cleaningcontact lenses is provided comprising contacting the lenses with acomposition containing an effective amount of one or more biguanidedisinfectants and from 0.0001% to about 10% by weight of one or morecyclodextrins for a time sufficient to clean the lenses. In a preferredembodiment, the composition is a multipurpose contact lens solution forcleaning and disinfecting contact lenses, and contains other componentssuch as including buffers, chelating and/or sequestering agents,tonicity adjusting agents, surfactants, pH adjusting agents andviscosity builders.

The invention still further provides a composition for rewetting,disinfecting and/or cleaning contact lenses comprising at least onebiguanide antimicrobial and an amount of cyclodextrin that isinsufficient of itself to effectively clean contact lenses if thatamount of cyclodextrin were present in the solution in the absence of atleast one other cleaning agent. In a preferred embodiment, thecomposition comprises a biguanide disinfectant selected from the groupconsisting of poly(hexamethylene) biguanide and alexidine. Thecomposition preferably comprises at least one buffer at least onechelating agent or sequestering agent. The composition may suitablycomprise at least one tonicity-adjusting agent, as well as surfactants,pH adjusting agents and viscosity builders.

DESCRIPTION OF THE INVENTION

The composition of the present invention is, in one embodiment, anaqueous biguanide-containing solution disinfecting solution, forexample, a multipurpose contact lens solution. The composition of theinvention contains one or more cyclodextrins together with one or morebiguanide disinfectants in a suitable carrier. Other active or inactivecomponents can also be employed in the compositions, including buffers,chelating and/or sequestering agents, tonicity adjusting agents,surfactants, pH adjusting agents and viscosity builders.

The cyclodextrins useful in the present invention are cyclicoligosaccharides that may be produced by the enzymatic degradation ofstarch and have multiple glucose or glucopyranose units, usually 6 to 8units. Depending on the particular preparation reaction conditionsemployed, cyclodextrins generally contain six, seven or eight of suchunits, connected by alpha-(1,4) bonds. The six, seven or eight unitcyclodextrins are commonly known as alpha-, beta-, andgamma-cyclodextrins, respectively.

Cyclodextrins have the shape of truncated cones with primary andsecondary hydroxyl groups located at opposite ends of the torus. Theglucosyl-o-bridges point into the center of the molecule and the primaryhydrogel groups project from one outer edge while the secondary hydroxylgroups project from the other edge. The result is a molecule with arelatively hydrophobic center and a hydrophilic outer surface. Theseshapes and hydrophilicl/hydrophobic domains provide for inclusion orincorporation of guest molecules into the center of the molecule.

Cyclodextrins are well known and are commercially produced by theenzymatic degradation of starch. For example, beta-cyclodextrin is themajor product of the reaction between the enzyme cyclodextrintransglycosylase and a starch solution pretreated with gamma-amylase.

As used herein, the term “cyclodextrins” includes all cyclodextrinderivatives, such as cyclodextrin carbonates, ethers, esters, andpolyethers; polymers or copolymers of polymerized cyclodextrins, such aspolymerized beta-cyclodextrins; and substituted cyclodextrins such asthose with functional groups bonded to one or more of the hydroxylgroups. Suitable function groups include, but are not limited to,methyl, ethyl, hydroxyethyl, and hydroxypropyl and acetyl groups. Thecyclodextrin derivatives can also include cyclodextrins with functionalgroups replacing one or more of the hydroxyl groups such asamino-cyclodextrin, iodo-cyclodextrin and cyclodextrin sulfate. Some ofthese functional groups may also contribute preserving or disinfectingproperties.

The preferred cyclodextrins are the beta-cyclodextrins and mostpreferred are beta-cyclodextrin selected from beta-cyclodextrin,hydroxypropyl beta-cyclodextrin, methyl beta-cyclodextrin andhydroxyethyl beta-cyclodextrin when the cyclodextrin compositions areemployed at elevated temperatures.

The present invention employs an effective amount of cyclodextrin toinhibit the binding of the biguanide with poly(ethylene) materials suchas low-density polyethylene (LDPE). The term “effective amount ofcyclodextrin” as used herein means an amount of cyclodextrin sufficientto inhibit the uptake of the biguanide disinfectant present in solutionfrom binding to a poly(ethylene), for a reasonable time. The preciseamount of cyclodextrin required to inhibit uptake will depend on severalfactors including the type of cyclodextrin, the amount of biguanidedisinfectant present in solution, the desired shelf life for thesolution, the specific type of poly(ethylene), and the like.

The term low-density poly(ethylene) and the acronym “LDPE” as usedherein means low-density polyethylene. LDPE is a polymer made entirelyor predominately from ethylene. LDPE is a thermoplastic. Its polymerstructure is predominately linear and often contains branches. WhileLDPE is considered to be semi-crystalline, LDPE can be used to fabricatea broad family of products by modifying its structural properties, andis commonly used for packaging products such as ophthalmic solutions.

LDPE is typically characterized by density in the range of from about0.910 to about 0.940 g/cc. The LDPE preferred for the present inventiontypically has a density of about 0.920 g/cc. A typical backbone (˜500monomers) of LDPE has short chain branches which reduce crystallinityand density.

In one embodiment of the invention the LDPE is formed into a resealabledispensing bottle of the type commonly used for over-the-counterophthalmic solutions including multipurpose contact lens solutions andrewetting drops.

The cyclodextrin concentrations useful herein may be adjusted by one ofordinary skill in the art depending upon the desired contact timebetween the biguanide-containing solution and the poly(ethylene).Cyclodextrins will generally be present in an amount from 0.0001% toabout 10% by weight with from about 0.01% to about 2.0% being preferred.

The cyclodextrin composition may contain a preserving or disinfectingamount of one or more antimicrobial agents in addition to the biguanideantimicrobial. The subject solution preferably includes at least oneantimicrobial agent. As used herein, antimicrobial agents are defined asnon-oxidative organic chemicals that derive their antimicrobial activitythrough a chemical or physiochemical interaction with the microbialorganisms. Preferred antimicrobials are the quaternary ammoniumcompounds and biguanides.

Representative examples of the quaternary ammonium compounds arecompositions comprised of benzalkonium halides or, for example, balancedmixtures of n-alkyl dimethyl benzyl ammonium chlorides. Other examplesinclude polymeric quaternary ammonium salts used in ophthalmicapplications such as poly[(dimethyliminio)-2-butene-1,4-diyl chloride],[4-tris(2-hydroxyethyl)ammonio]-2-butenyl-w-[tris(2-hydroxyethyl)ammonio]dichloride (chemicalregistry number 75345-27-6) generally available as Polyquaternium 1®from ONYX Corporation.

Representative biguanides are the bis(biguanides), such as alexidine orchlorhexidine or salts thereof, and polymeric biguanides such aspolymeric hexamethylene biguanides (PHMB).

Polymeric hexamethylene biguanides (commercially available from Zeneca,Wilmington, DE), their polymers and water-soluble salts being mostpreferred.

Generally, the hexamethylene biguanide polymers, also referred to aspolyaminopropyl biguanide (PAPB), have molecular weights of up to about100,000. Such compounds are known and are disclosed in U.S. Pat. No.4,758,595 which patent is incorporated herein be reference.

A disinfecting amount of antimicrobial agent is an amount that will atleast partially reduce the microorganism population in the formulationsemployed. Preferably, a disinfecting amount is that which will reducethe microbial burden by two log orders in four hours and more preferablyby one log order in one hour. Most preferably, a disinfecting amount isan amount which will eliminate the microbial burden on a contact lenswhen used in regimen for the recommended soaking time (FDA ChemicalDisinfection Efficacy Test—July, 1985 Contact Lens Solution DraftGuidelines). Typically, such agents are present in concentrationsranging from about 0.00001 to about 0.5% (w/v), and more preferably,from about 0.00003 to about 0.5% (w/v).

A second disinfectant/germicide can be employed as a solutionpreservative, but it may also function to potentiate, compliment orbroaden the spectrum of microbiocidal activity of another germicide.This includes microbiocidally effective amounts of germicides which arecompatible with and do not precipitate in the solution, inconcentrations ranging from about 0.00001 to about 0.5 weight percent,and more preferably, from about 0.0001 to about 0.1 weight percent.Suitable complementary germicidal agents include, but are not limited tothimerosal or other phenylmercuric salts, sorbic acid, alkyltriethanolamines, and mixtures thereof.

The acid-addition salts of the germicides used in the presentcomposition may be derived from an inorganic or organic acid. In mostcircumstances it is preferable that the salts be derived from an acidwhich is readily water-soluble and which affords an anion which issuitable for human usage, for example a pharmaceutically acceptableanion. Examples of such acids are hydrochloric, hydrobromic, phosphoric,sulphuric, acetic, D-gluconic, 2-pyrrolidino-5-carboxylic,methanesulphonic, carbonic, lactic and glutamic acids. The hydrochloridesalt is preferred.

In the present application, the amount of the germicide or othercomponents in a solution according to the present invention refers tothe amount formulated and introduced into the solution at the time thesolution is made.

Suitable chemical antimicrobial agents, as the term is used herein,include quaternary ammonium salts and polymers used in ophthalmicapplications such as poly[(dimethyliminio)-2-butene-1,4-diyl chloride],[4-tris (2-hydroxyethyl) ammonio]-2-butenyl-W-[tris(2-hydroxyethyl)ammonio]dichloride (chemical registry number 75345-27-6), commerciallyavailable from ONYX Corporation; halides; trialkylammonium halides;biguanides such as salts of alexidine, alexidine free base, salts ofchlorhexidine, hexamethylene biguanides and their polymers; and thelike. The salts of alexidine and chlorhexidine can be either organic orinorganic and are typically gluconates, nitrates, acetates, phosphates,sulfates, halides and the like.

Suitable oxidative antimicrobial agents, as the term is used herein,include any peroxide sources which produce active oxygen in solution andany iodine liberating sources which produce preserving or disinfectingamounts of iodine compounds in solution. Examples of such agents includehydrogen peroxide and its alkali metal salts; alkali metal perboratesand persulfates; alkali metal carbonate peroxide; diperisophthalic acid;peroxydiphosphate salts; sodium aluminium aminohydroperoxide; iodine andiodophors. Preferred oxidative antimicrobial agents are peroxides andiodophors. The antimicrobial agents can also be employed after thecleaning step using the cyclodextrin composition. In this application,the cleaning step would be followed with a disinfecting step in aconventional regimen.

A preserving amount of an antimicrobial agent is an amount that willsubstantially inhibit the microorganism population from growing while adisinfecting amount is an amount that will reduce the microorganismpopulation. Preferably, a preserving amount of antimicrobial agent willsubstantially inhibit the microorganism population growth for at leastthirty (30) days after exposure to environmental air. Preferably, adisinfecting amount of an antimicrobial agent is that which will reducethe microbial burden by about two log orders in four hours and, morepreferably, by about one log order in one hour. Typically, such agentsare present in concentrations ranging from about 0.00001% to about 0.5%(w/v), and more preferably, from about 0.00003% to about 0.05% (w/v).

The pH of the present solutions should be maintained within the range of5.0 to 8.0, more preferably about 6.0 to 8.0, most preferably about 6.5to 7.8, suitable buffers may be added, such as boric acid, sodiumborate, potassium citrate, citric acid, sodium bicarbonate, TRIS, andvarious mixed phosphate buffers (including combinations of Na₂HPO₄,NaH₂PO₄ and KH₂PO₄) and mixtures thereof. Borate buffers are preferred,particularly for enhancing the efficacy of biguanides.

Generally, buffers will be used in amounts ranging from about 0.05 to2.5 percent by weight, and preferably, from 0.1 to 1.5 percent. Thedisinfecting/preserving solutions of this invention preferably contain aborate or mixed phosphate buffer, containing one or more of boric acid,sodium borate, potassium tetraborate, potassium metaborate or mixturesof the same. In one embodiment, the solution of the invention mayinclude a buffering system having a buffering capacity up to 40 ml of0.01N HCl to change pH from pH 7.4 to 6.4 and up to 25 ml of 0.01 N NaOHto change pH from pH 7.4 to 8.4 and comprising 0.05˜2.5% by weight ofphosphate salt and 0.1˜5.0% by weight of boric acid. The compositionoptionally further comprises an alkali or alkaline earth metalcarbonates including sodium bicarbonate, sodium carbonate, potassiumcarbonate, potassium bicarbonate, and sodium bicarbonate. The mostpreferred carbonate is sodium carbonate.

If a carbonate buffer is used, it is suitably present in the amount of abuffering system having a buffering capacity up to 40 ml of 0.01 NHCl tochange pH from pH 7.4 to 6.4 and up to 25 ml of 0.01˜NaOH to change pHfrom pH 7.4 to 8.4 and comprising 0.05˜2.5% by weight of phosphate saltand 0.1˜5.0% by weight of boric acid.

The composition of the present invention may optionally includes aphosphonic acid, or its physiologically compatible salt, that isrepresented by the following Formula (I):

wherein Z is a connecting radical equal in valence to n, wherein n is aninteger from 1 to 6, preferably 1 to 3.

If the solution contains a phosphonic acid buffer, the phosphonic acidbuffer is suitably present in a concentration of at least 0.003 percentweight by volume of the subject phosphonic compound in the totalsolution, preferably 0.005 to 2.5 percent weight by volume and morepreferably about 0.01 to 0.5 percent weight by volume in the totalsolution.

In a preferred embodiment, the solution comprises both a phosphatebuffer and a borate buffer.

In addition to buffering agents, in some instances it may be desirableto include chelating and/or sequestering agents in the present solutionsin order to bind metal ions which might otherwise react with the lensand/or protein deposits and collect on the lens. Dequest 2016 and itssalts (disodium) are preferred examples. They are usually added inamounts ranging from about 0.01 to about 0.3 weight percent. Othersuitable sequestering agents include gluconic acid, citric acid,tartaric acid (EDTA) and their salts, e.g. sodium salts.

Typically, the aqueous solutions of the present invention for treatingcontact lenses are also adjusted with tonicity agents, to approximatethe osmotic pressure of normal lacrimal fluids which is equivalent to a0.9 percent solution of sodium chloride or 2.5 percent of glycerolsolution. The solutions are made substantially isotonic withphysiological saline used alone or in combination, otherwise if simplyblended with sterile water and made hypotonic or made hypertonic thelenses will lose their desirable optical parameters. Correspondingly,excess saline may result in the formation of a hypertonic solution thatwill cause stinging and eye irritation.

Examples of suitable tonicity adjusting agents include, but are notlimited to: sodium and potassium chloride, dextrose, glycerin, calciumand magnesium chloride. These agents are typically used individually inamounts ranging from about 0.01 to 2.5% (w/v) and preferably, form about0.2 to about 1.5% (w/v). Preferably, the tonicity agent will be employedin an amount to provide a final osmotic value of 200 to 450 mOsm/kg andmore preferably between about 250 to about 350 mOsm/kg, and mostpreferably between about 280 to about 320 mOsm/Kg.

The present solution comprises at least one surfactant. Suitablesurfactants can be either amphoteric, cationic, anionic, or nonionicwhich may be present (individually or in combination) in amounts up to15 percent, preferably up to 5 percent weight by volume (w/v) of thetotal composition (solution). Preferred surfactants are amphoteric ornonionic surfactants, which when used impart cleaning and conditioningproperties. The surfactant should be soluble in the eye care solutionand non-irritating to eye tissues. Many nonionic surfactants compriseone or more chains or polymeric components having oxyalkylene (-O-R-)repeats units wherein R has 2 to 6 carbon atoms. Preferred non-ionicsurfactants comprise block polymers of two or more different kinds ofoxyalkylene repeat units, which ratio of different repeat unitsdetermines the HLB of the surfactant. Satisfactory non-ionic surfactantsinclude polyethylene glycol esters of fatty acids, e.g. coconut,polysorbate, polyoxyethylene or polyoxypropylene ethers of higheralkanes (C₁₂-C₁₈). Examples of the preferred class include polysorbate20 (available under the trademark Tween® 20), polyoxyethylene (23)lauryl ether (Brij® 35), polyoxyethyene (40) stearate (Myrj® 52),polyoxyethylene (25) propylene glycol stearate (Atlas® G 2612). Onenon-ionic surfactant in particular consisting of apoly(oxypropylene)-poly(oxyethylene) adduct of ethylene diamine having amolecular weight from about 7,500 to about 27,000 wherein at least 40weight percent of said adduct is poly(oxyethylene) has been found to beparticularly advantageous for use in cleaning and conditioning both softand hard contact lenses when used in amounts from about 0.01 to about 15weight percent. The CTFA Cosmetic Ingredient Dictionary's adopted namefor this group of surfactants is poloxamine. Such surfactants areavailable from BASF Wyandotte Corp., Wyandotte, Mich., under theregistered trademark “Tetronic”. An analogous of series of surfactants,suitable for use in the present invention, is the poloxamer series whichis a poly(oxyethylene) poly(oxypropylene) block polymers available underthe trademark “Pluronic” (commercially available form BASF).

Various other ionic as well as amphoteric and anionic surfactantssuitable for in the invention can be readily ascertained, in view of theforegoing description, from McCutcheon's Detergents and Emulsifiers,North American Edition, McCutcheon Division, MC Publishing Co., GlenRock, N.J. 07452 and the CTFA International Cosmetic IngredientHandbook, Published by The Cosmetic, Toiletry, and FragranceAssociation, Wash. D.C.

Amphoteric surfactants suitable for use in a composition according tothe present invention include materials of the type are offeredcommercially under the trade name “Miranol.” Another useful class ofamphoteric surfactants is exemplified by cocoamidopropyl betaine,commercially available from various sources.

The foregoing surfactants will generally be present in a total amountfrom 0.01 to 5.0 percent weight by volume (w/v), preferably 0.1 to 5.0percent, and most preferably 0.1 to 1.5 percent.

It may also be desirable to include water-soluble viscosity builders inthe solutions of the present invention. Because of their demulcenteffect, viscosity builders have a tendency to enhance the lens wearer'scomfort by means of a film on the lens surface cushioning impact againstthe eye. Included among the water-soluble viscosity builders are thecellulose polymers like hydroxyethyl or hydroxypropyl cellulose,carboxymethyl cellulose and the like. Such viscosity builders may beemployed in amounts ranging from about 0.01 to about 4.0 weight percentor less. The present solutions may also include optional demulcents.

In a first embodiment of a method according to the present invention,the method comprises cleaning a contact lens with an aqueous solutioncomprising 0.005 to 1.0 percent by weight of at least one phosphonicacid compound, or its physiologically compatible salt, having 1 to 12,preferably 1 to 10 carbon atoms. The carbon atoms may be in the form ofa substituted or unsubstituted branched or unbranched aliphatic, cyclicaliphatic, or aromatic groups or combinations thereof. Exemplaryphosphonic acid compounds are those according to Formula (I) above.Preferably the phosphonic acid compound has 1 or 2 phosphonic acidgroups which may be in salt form.

Preferably, the present method comprises soaking (no rubbing) a lens inthe solution for a total period of time that is within a range of 2hours to overnight, prior to direct placement of the lens in the eye. Bythe term “direct placement” is herein meant that the solution is notdiluted or rinsed off the lens with a different contact-lens solutionprior to “insertion” or placement on the eye.

In yet another embodiment of a method according to the presentinvention, the claimed solution may be used to clean a frequentreplacement lens (FRL) that is planned for replacement after not morethan about three months of use in the eye, or that is planned forreplacement after not more than about 30 days of use in the eye, or thatis planned for replacement after not more than about two weeks in theeye. Preferably, the lens is made from a polymer comprising about 0.0 to5 mole percent repeat units derived from methacrylic acid (MAA), 10 to99 mole percent of repeat units derived from hydroxyethyl methacrylate,and about 0.5 to 5 mole percent of cross-linking repeat units.Cross-linking repeat units may be derived, for example, from suchmonomers as ethyleneglycol dimethacrylate, divinylbenzene, andtrimethylpropane trimethacrylate.

Separately from, or supplementally to, immersing a contact lens in acontact lens solution according to the present invention while thecontact lens is outside the eye, the accumulation of proteins onhydrophilic contact lens can be further prevented by applying such asolution as eye drops. Thus, an opthalmologically safe solutioncomprising the claimed compound can be packaged in a container adaptedfor applying the solution as drops to the eye.

The hydroxypropyl methylcellulose (HPMC) functions to provide a desiredlevel of viscosity and to provide demulcent activity. It ischaracterized as a mixed ether of cellulose containing a variableproportion of methoxyl and 2-hydroxypropoxyl groups and is purchasedfrom Dow Chemical under the trademark Methocel E 15 LV -Premium. It isto be understood that the invention is not limited to any specifichydroxypropyl methylcellulose and that any equivalent HPMC ofpharmaceutical grade may be used.

The ophthalmic solutions of this invention preferably contain a buffersystem to control pH. Any pharmaceutically acceptable buffer system maybe utilized. A preferred buffer system is provided by sodiumborate/boric acid in amounts necessary to produce a pH of about 6.0 to8.0. A preferred pH range is about 6.5-7.8 and a most preferred range isabout 7.1-7.5.

The ophthalmic solutions of this invention are isotonic with respect tothe fluids of the human eye. These solutions are characterized byosmolalities of 270-330 mOsm/kg. Osmolality of the solution of theinvention is adjusted by means of sodium chloride and potassiumchloride.

The solutions of the present invention may be formulated into specificcontact lens care products, such as wetting solutions, soakingsolutions, cleaning and conditioning solutions, as well as purpose typelens care solutions, etc. and mixtures thereof.

The solutions according to the present invention are physiologicallycompatible. Specifically, the solution must be “ophthalmically safe” foruse with a contact lens, meaning that a contact lens treated with thesolution is generally suitable and safe for direct placement on the eyewithout rinsing, that is, the solution is safe and comfortable for dailycontact with the eye via a contact lens that has been wetted with thesolution. An ophthalmically safe solution has a tonicity and pH that iscompatible with the eye and comprises materials, and amounts thereof,that are non-cytotoxic according to ISO standards and U.S. FDA (Food &Drug Administration) regulations. The solution should be sterile in thatthe absence of microbial contaminants in the product prior to releasemust be statistically demonstrated to the degree necessary for suchproducts.

The present invention can be used with all contact lenses such asconventional hard, soft, rigid and soft gas permeable, and silicone(including both hydrogel and non-hydrogel) lenses, but is preferablyemployed with soft lenses. Such lenses are commonly prepared frommonomers such as hydroxyethyl methacrylate, hydroxyethylmethylmethacrylate, vinylpyrrolidone, glycerolmethacrylate, methacrylic acidor acid esters and the like. Such lenses absorb significant amounts ofwater, which amounts range from about 4 to about 80 percent by weight.Preferably, the invention is formulated as a “multipurpose solution,”meaning that the solution may be used for cleaning, chemicaldisinfection, storing, and rinsing a contact lens. Such solutions may bepart of a “multipurpose solution system” or “multipurpose solutionpackage.” The procedure for using a multi-purpose solution, system orpackage is referred to as a “multi-functional disinfection regimen.”Multi-purpose solutions do not exclude the possibility that somewearers, for example, wearers particularly sensitive to chemicaldisinfectants or other chemical agents, may prefer to rinse or wet acontact lens with another solution, for example, a sterile salinesolution prior to insertion of the lens. The term “multipurposesolution” also does not exclude the possibility of periodic cleaners notused on a daily basis or supplemental cleaners for removing proteins,for example enzyme cleaners, which are typically used on a weekly basis.By the term “cleaning” is meant that the solution contains one or morecleaning agents in sufficient concentrations to loosen and removeloosely held lens deposits and other contaminants on the surface of acontact lens, especially if used in conjunction with digitalmanipulation (for example, manual rubbing of the lens with a solution)or with an accessory device that agitates the solution in contact withthe lens, for example, a mechanical cleaning aid. The critical micelleconcentration of a surfactant-containing solution is one way to evaluateits cleaning effectiveness.

A multipurpose solution preferably has a viscosity of less than 75 cps,preferably 1 to 50 cps, and most preferably 1 to 25 cps and ispreferably is at least 95 percent weight by volume water in the totalcomposition.

As stated, the multipurpose solution of the invention is useful forcleaning contact lenses. Although the multipurpose solution effectivelycleans and disinfects by simply soaking a lens in the subject solution,the multipurpose solution cleans more effectively if a few drops of thesolution are initially placed on each side of the lens, and the lens isrubbed for a period of time, for example, approximately 20 seconds. Thelens can then be subsequently immersed within several milliliters of thesubject solution. Preferably, the lens is permitted to soak in thesolution for at least four hours. Furthermore, the lens is preferablyrinsed with fresh solution after the rubbing step and again after beingimmersed within the solution. If the subject solution includes anantimicrobial agent, the subject solution not only cleans the lens, butalso disinfects. However, it will be appreciated that other“non-chemical” disinfection means may be used, e.g. heat disinfection.

Although not generally necessary, enzymatic cleaners may also be usedwith the multipurpose contact lens solutions of the invention,especially for patients susceptible to high levels of proteindeposition. If used, enzymatic tablets may be placed directly within thesubject solution, is a manner like that described in U.S. Pat. No.5,096,607.

EXAMPLES

The following detailed examples are presented to illustrate the presentinvention.

Formulation

Ingredients % W/W Sodium Chloride 0.45% Sodium Borate 0.09% Boric Acid0.85% Alexidine HCl 2-10 ppm Beta-Cyclodextrin 0.1-0.3% Purified waterQs = 1000 ml

Materials

Alexidine Solution (2-10 ppm)

Alexidine/0.1% β-Cyclodextrin Solution

Alexidine/0.3% β-Cyclodextrin Solution

LDPE Bottles

Method

1) Eighty-five gm of water was added into a beaker.

2) Sodium chloride, sodium borate, boric acid and beta-cyclodextrin wereadded and the mixture was stirred until each ingredient dissolved.

3) Alexidine HCl was then added into the above mixture and mixed formore than five hours.

4) The final mixture was brought to 100 gm of total weight by addingpurified water. The pH of final solution is 7.0 and Osmo. equals to 294mOsm/kg.

5) 15-mL of each test solution, as well as the control solution, wereplaced into the 15-ml LDPE bottle for a total of 5 samples per solution.

6) Solutions (in LDPE bottles) were allowed to stay in bottles forapproximately 7-10 days.

7) 1-mL from each of the LDPE bottles was removed and analyzed for freeAlexidine concentrations.

Effect of Beta-Cyclodextrin on the uptake of Alexidine by SureVueLenses:

Uptake of Alexidine by Uptake of Alexidine Uptake of Alexidine LDPEBottle by LDPE Bottle (15 ml) by LDPE Bottle (15 ml) (15 ml) (0.1%Beta-Cyclodextrin) (0.3% Beta-Cyclodextrin) 29.7 ppm 21.02 ppm 12.3 ppm29.2% Inhibition 58.6% Inhibition

ISO Stand Alone Microbiology Test:

Alexidine Alexidine Solution With Solution Beta-Cyclodextrin Lot Number2158RF081 2158RF083 Fill Volume 15 ml 15 ml Bottle Size 15 ml 15 mlManufactured 7/15/00 7/15/00 Start Date 7/26/00 7/26/00 Sample Reference00-2913 00-2913 Test Disposition Pass Pass Staphylococcus Aureus 10Minutes >4.7 2.5 1 Hour >4.7 4.3 2 Hours >4.7 >4.7 4 Hours >4.7 >4.7Pseudomonas Aeruginasa 10 Minutes >4.6 3.6 1 Hour >4.6 >4.6 2Hours >4.6 >4.6 4 Hours >4.6 >4.6 Serratia Marcescens 10 Minutes 2.3 3.61 Hour 4.6 >4.6 2 Hours >4.6 >4.6 4 Hours >4.6 >4.6 Candida Albicans 10Minutes 2.8 1.4 1 Hour 3.5 3.0 2 Hours 4.6 4.3 4 Hours >4.6 >4.6 24Hours >4.6 >4.6 Fusarium Solani 10 Minutes 2.9 3.0 1 Hour 3.8 3.7 2Hours 3.7 4.1 4 Hours 4.0 4.1 24 Hours >4.1 >4.1

The examples and description are illustrative; the scope of theinvention is defined solely by the following claims.

What is claimed:
 1. A method for inhibiting the binding of a biguanidedisinfectant in aqueous solution to a low-density poly(ethylene) solidin contact with said solution comprising providing in said solution anamount of cyclodextrin sufficient to inhibit binding of the biguanidedisinfectant to the low-density poly(ethylene) solid and storing saidsolution in a container made of the low-density poly(ethylene) for atleast seven days.
 2. The method of claim 1 wherein the biguanidedisinfectant is selected from the group consisting ofpoly(hexamethylene) biguanide and alexidine.
 3. The method of claim 1wherein said poly(ethylene) is low-density polyethylene (LDPE) asdefined herein.
 4. The method of claim 1 wherein said solution furthercomprises at least one buffer.
 5. The method of claim 1 wherein saidsolution further comprises at least one chelating agent or sequesteringagent.
 6. The method of claim 1 wherein said solution further comprisesat least one tonicity adjusting agent.
 7. The method of claim 1 whereinsaid solution further comprises at least one surfactant.
 8. The methodof claim 1 wherein said solution comprises at least one pH adjustingagent.
 9. The method of claim 1 wherein said solution comprises at leastone viscosity builder.
 10. The method of claim 1 wherein said solutioncomprises from about 0.0001 to about 10 weight percent cyclodextrin. 11.The method of claim 10 wherein said solution comprises from about 0.01to about 2.0 weight percent cyclodextrin.